Effect of Dietary Omega-3 Fatty Acids on Castrate Resistant Prostate Cancer and Tumor Associated Macrophages

BACKGROUND: M2-like macrophages are associated with the pathogenesis of castrate resistant prostate cancer (CRPC). We sought to determine if dietary omega-3 fatty acids (ω−3 FAs) delay the development and progression of CRPC and inhibit tumor associated M2-like macrophages. METHODS: MycCap cells were grown subcutaneously in immunocompetent FVB mice. Mice were castrated when tumors reached 300mm(3). To study effects of dietary ω−3 FAs on development of CRPC, ω−3 or ω−6 diets were started two days after castration and mice sacrificed after early regrowth of tumors. To study ω−3 FA effects on progression of CRPC, tumors were allowed to regrow after castration before starting the diets. M2 (CD206+) macrophages were isolated from allografts to examine ω−3 FA effects on macrophage function. Omega-3 fatty acid effects on androgen-deprived RAW264.7 M2 macrophages was studied by RTqPCR and a migration/ invasion assay. RESULTS: The ω−3 diet combined with castration lead to greater MycCap tumor regression (182.2±33.6 mm(3)) than the ω−6 diet (148.3±35.2; p=0.003) and significantly delayed the time to CRPC (p=0.006). Likewise, the ω−3 diet significantly delayed progression of established castrate resistant MycCaP tumors (p=0.003). The ω−3 diet (as compared to the ω−6 diet) significantly reduced tumor associated M2-like macrophage expression of CSF-1R in the CRPC development model, and matrix metallopeptidase-9 (MMP-9) and vascular endothelial growth factor (VEGF) in the CRPC progression model. Migration of androgen depleted RAW264.7 M2 macrophages towards MycCaP cells was reversed by addition of docosahexaenoic acid (ω−3). CONCLUSIONS: Dietary omega-3 FAs (as compared to omega-6 FAs) decreased the development and progression of CRPC in an immunocompetent mouse model, and had inhibitory effects on M2-like macrophage function. Clinical trials are warranted evaluating if a fish oil-based diet can delay the time to castration resistance in men on androgen deprivation therapy, whereas further pre-clinical studies are warranted evaluating fish oil for more advanced CRPC.